N-methyl-D-aspartate (NMDA) receptors are glutamate gated ion channels that play an important role in synaptic transmission, synaptic plasticity, and synapse formation. Inadequate or excessive NMDA receptor activity contributes to the pathogenesis of a wide variety of disorders including fetal alcohol syndrome, ethanol tolerance, alcoholism, schizophrenia, major depression, and posttraumatic stress disorder. For example, animals with reduced NMDA receptor surface expression exhibit schizophrenic-like behavior such as increased motor activity and deficits in social and sexual interactions. Efficient assembly and trafficking of NMDA receptors from the endoplasmic reticulum (ER) to the plasma membrane is a key step in regulating NMDA receptor activity. However, the cellular and molecular mechanisms regulating the release of NMDA receptors from the ER are entirely unknown. The objective of this proposal is to determine the key regulatory steps underlying NMDA receptor ER release and surface expression. To this end, I will identify intracellular domains that prevent ER release of NMDA receptors using a combination of immunocytochemical, biochemical, pharmacological and cell culture techniques. Second, I will determine the role intracellular second messengers or other NMDA receptor subunits play in regulating ER release of native channels. Understanding how NMDA receptors exit the ER and traffic to the plasma membrane may ultimately facilitate the design of alternative therapies useful in the treatment of alcoholism, fetal alcohol syndrome, and many psychiatric disorders.